Sequence Generation

• If computer-generated, random number list, flipping coins, randomly picking envelopes, etc. is specified → YES
• If the description only includes ‘random,’ ‘randomly generated,’ ‘randomized,’ etc., do not assume additional details → UNCLEAR
• If the description is quasi-randomized (e.g. alternate randomization, day of the year, day of the month, birth date, birth month, beginning letter of last name, availability of investigator or specialist, etc.) → NO

Allocation Concealment

• If the assignment is conducted by central telephone, pharmacy, etc. → YES
• If dark (or opaque), sealed, sequentially numbered envelopes are used → YES
• If the envelopes are not stated to dark and sealed, or sequentially numbered → UNCLEAR

Note: sequential numbering of the envelopes is only required for adequate allocation concealment if the method of randomization was anything other than randomly picking envelopes (i.e., the envelopes were only used for allocation concealment and not as part of the randomization process).

Blinding

• If the study was stated to be blinded (masked) and the blinding is considered to be possible, and not likely to be broken → YES
• If the study is only stated to be blinded, double-blinded, double-dummy, etc. without any further details → UNCLEAR
• If the study states the use of a placebo (dummy) but with no further details → UNCLEAR
• If no mention of blinding → NO

Incomplete Outcome Data

• Look for intention-to-treat analysis (all randomized pts. are analyzed) → YES
• If all participants were accounted for (i.e. no drop-outs or censored analysis conducted) → YES
• If the numbers and reasons for withdrawal/dropouts were described and comparable across groups (and ≤ approximately 10 percent) → YES
• If there is between 10 percent and 30 percent dropout and no ITT analysis → UNCLEAR
• If there is greater 30 percent dropout and no ITT analysis → NO

Selective Outcome Reporting

• If the study protocol is available (referenced in the manuscript), compare the outcomes reported in the publication to those specified in the protocol. If they match → YES
• If the study protocol is available (referenced in the manuscript), compare the outcomes reported in the publication to those specified in the protocol. If they do not match, but there is reference to another publication with this information presented → YES
• If the study protocol is not available, compare the outcomes reported in the Methods and Results sections. If they match → YES

Other Sources of Bias

• Assess for baseline imbalances that could have biased the results (or were not accounted for).
• Assess for early stopping for benefit.
• Assess for appropriateness of cross-over design (e.g., inadequate washout period).
• Assess for inappropriate influence of funders that could have biased the results:

  • If sponsor is acknowledged and there is a clear statement regarding no involvement of sponsor in trial conduct or data management/analysis, or coauthorship → YES
  • If sponsor is acknowledged with no further information provided or (co)author works for a pharmaceutical company → NO
  • If there is no mention of funding source → UNCLEAR
• Note any “other” sources of bias.